Project Summary/Abstract The HIV pandemic has intensified the growing burden of cancer in low- and middle-income countries (LMICs), where nearly three-quarters of all cancer deaths occur. The majority of patients in LMICs have advanced cancer stage and limited opportunity for survival. Meaningful improvements in cancer mortality in LMICs will require prompt diagnosis and efficient linkage to care, however research identifying effective strategies has not been conducted. Botswana has key resources in place? free-of-charge medical care including comprehensive cancer care, accessible primary clinics, and an internationally-emulated ART program? yet large gaps in timely cancer care and thus provides a key opportunity to innovate strategies to detect cancer earlier and engage patients in care. The Potlako pilot trial (ORBIT phase IIa), evaluating an intervention targeting diagnostic and pre-treatment intervals in a single district (27 communities) in Botswana, has successfully increased the number of patients entering cancer care and number treated with curative intent compared to historical controls. As a next step, the Potlako+ trial? a community-randomized (26 geographically diverse rural communities, 1:1), pragmatic, ORBIT phase IIb, type 1 hybrid effectiveness-implementation trial? will assess a complex, theory-informed intervention to promote earlier clinic presentation with symptoms suggestive of cancer, enable efficient diagnosis, and facilitate prompt initiation of oncologic treatment. The Potlako+ trial targets high burden cancers accounting for 60% of cancer deaths (breast, cervix, anus, penis, vulva, and head and neck) which are typically curable with early detection of symptoms. We utilize cancer stage at time of treatment initiation, incidence of curative intent treatment, and the duration of Models of Pathways to Treatment intervals as primary effectiveness endpoints. Implementation will be evaluated using the RE-AIM framework. The project will achieve three aims: 1) Assess the effectiveness of cancer symptom awareness intervention with rural residents (persons living with HIV and HIV-uninfected) aged 30 years and older in decreasing time to presentation with moderate and high probability cancer syndromes, 2) Assess impact of a comprehensive cancer patient navigation platform on reducing time to diagnosis and initiation of cancer treatment (diagnostic and pre-treatment intervals), and 3) Evaluate whether the combined multilevel intervention improves early stage treatment and cumulative incidence of curative intent treatment. Understanding the impact and implementation of these interventions will inform strategies of care for LMIC populations at increasing risk of cancer death and contribute to developing models of primary care in resource- constrained environments.